Membrane depolarization drives tumor-suppressive cell competition via Hedgehog signaling activation

Kun Zhao; Dian Lv; Du Kong; Yifan Guo; Xianping Wang; Sihua Zhao; Jiadong Zheng; Jia Jing; Sha Song; Jingjie Mu; Yixin Wu; Xihui Chen; Xuan Guo; Yunpeng Huang; Wenyan Xu; Min Jiang; Xiaoqin Li; Xianjue Ma

doi:10.1016/j.jgg.2026.05.010

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Membrane depolarization drives tumor-suppressive cell competition via Hedgehog signaling activation

doi: 10.1016/j.jgg.2026.05.010

a. State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China;
b. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310030, China;
c. Department of Hepatobiliary Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China;
d. School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China;
e. Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning 110003, China;
f. School of Life Science, Hangzhou Institute for Advanced Studies, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310000, China;
g. School of Public Administration, Shandong Technology and Business University, Yantai, Shandong 264005, China

Funds:

We thank Qiang Zhang, Tian Xu, Lei Xue, Thuan Beng Saw, BDSC, VDRC, NIG-Fly Stock Center, and DSHB for providing reagents. We are grateful to Wenhan Liu for maintaining fly stocks and to Shiyu Peng for critical discussions on V_m experiments. The schematic was created with BioRender (www.biorender.com). This work was supported by startup funds from Westlake University and the National Natural Science Foundation of China (32322027 and 32170824), the Zhejiang Provincial Natural Science Foundation Project (LQKWL26C0701 to X.M.), the State Key Laboratory of Gene Expression (ZX-2025004 to X.M.), the Natural Science Foundation of Hangzhou (2025SZRJJ0011 to X.M.), and the HRHI program of Westlake Laboratory of Life Sciences and Biomedicine (1011103360222B1 to X.M.).

Received Date: 2026-04-20
Accepted Date: 2026-05-19
Rev Recd Date: 2026-05-18

Available Online: 2026-05-26

Abstract

Abstract

Tumor-suppressive cell competition (TSCC) is an evolutionarily conserved process that safeguards tissue integrity by selectively eliminating less-fit, precancerous cells. While bioelectric regulation via plasma membrane potential (V_m) is emerging as a key modulator of cellular fitness, its mechanistic role in TSCC remains underexplored. Here, we combine Drosophila genetics, single-cell RNA sequencing (scRNA-seq), and mammalian co-culture models to indicate that V_m depolarization acts as a critical driver of TSCC through Hedgehog (Hh) signaling. In Drosophila eye epithelia, scribble-deficient (scrib^−/−) “loser” clones exhibit mitochondrial respiratory chain defects, leading to reduced ATP synthesis and subsequent plasma membrane depolarization. This depolarization stabilizes Smoothened at the membrane, aberrantly activating Hedgehog signaling and triggering the elimination of scrib^−/− clones. Notably, we observe a striking mechanistic parallel in mammalian epithelia: Scrib-depleted Madin-Darby Canine Kidney (MDCK) cells similarly undergo V_m depolarization-dependent elimination associated with Hh pathway activation. Together, our work advances the understanding of bioelectricity in cancer surveillance and suggests that targeting membrane potential could offer a promising therapeutic strategy for cancer prevention by exploiting cell competition mechanisms.
- Drosophila,
- Membrane potential,
- Scribble,
- Cell competition,
- Hedgehog signaling,
- Tumor suppression,
- Single-cell RNA sequencing

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